DESCRIPTION: (Adapted from the applicant's abstract and Specific Aims.) Lung transplantation has become a therapeutic option for a number of end- stage pulmonary disorders. Although the popularity of lung transplantation has exponentially increased, lung transplant patients have far more complications due to acute and chronic allograft rejection as compared to recipients of other solid organs. This application will focus on the role of tumor necrosis factor alpha (TNF) and intercellular adhesion molecule-1 (ICAM-1) in the pathogenesis of acute lung allograft rejection. The working hypothesis is that the production of TNF by immune mononuclear cells and the expression of ICAM-1 by both immune and non- immune cells contributes to the pathogenesis of lung allograft rejection through both nonspecific and antigen specific inflammatory events. The Specific Aims are to: 1) characterize the compartment, cellular source(s), and time course for the expression of TNF mRNA, antigen, and specific bioactivity during the evolution of acute rat lung allograft rejection; 2) establish in vivo whether neutralizing TNF antibodies will alter the pathogenesis of the initiation and maintenance of acute rat lung allograft rejection; 3) determine the cellular source(s) and time course for the expression of ICAM-1 mRNA and antigen during the development of acute rat lung allograft rejection in the presence or absence of in vivo neutralizing TNF antibodies; and 4) assess in vivo whether neutralizing ICAM-1 monoclonal antibodies, in the presence or absence of neutralizing TNF antibodies, modifies the pathogenesis of acute rat lung allograft rejection. These findings may provide insight into the use of therapeutic interventions during periods of allograft rejection.